Lung cancer is the leading cause of cancer-related deaths in the U.S., with an overall 5 year survival rate of pound15%. The ability to detect early stage lesions in otherwise asymptomatic patients would increase the likelihood of survival. Recently, annual low-dose CT has been studied to determine its value for screening asymptomatic individuals that are at high risk for cancer (i.e., significant smoking history). However, the efficacy and effects of annual CT lung screening are largely unknown. There may be a risk associated with the CT screening process, as the use of ionizing radiation could potentially cause the development of tumors. We thus propose to determine the effect of clinically relevant CT screening procedures on the potential to cause radiation-induced carcinogenesis using three different mouse models of lung carcinogenesis. We will utilize a transgenic mouse model representative of the earliest stages of lung tumorigenesis and employ both a standard complete carcinogenesis and an initiation/promotion protocol of lung tumor formation, utilizing classes of chemical carcinogens that are prevalent in cigarette smoke and are implicated in lung tumor pathogenesis. We will also determine if the radiation doses received during routine whole-body or lung CT screening increase biomarkers of oxidative stress (pNF-kb, COX-2, iNOS, or carbonyl protein oxidation) that can be mechanistically related to any effects (or lack thereof) on lung tumor formation and/or promotion/progression. The resulting data will have a significant impact on the clinical use of CT in determining the risk of cancer development from clinical low-dose CT exposure. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer-related deaths in the U.S. Annual low-dose CT has been recently studied to determine its value for screening asymptomatic individuals that are at high risk for lung cancer, however, the effects of annual CT lung screening are largely unknown. The proposed studies will determine if CT, a technique that could reduce the single biggest cause of cancer mortality in the US, can be justified as a screening tool to detect lung lesions in asymptomatic smokers and ex- smokers because the benefits outweigh the risk of radiation-induced lung cancer.